Lupus (2015) 24, 321–326 http://lup.sagepub.com
CONCISE REPORT
Characteristics of pleural effusions in systemic lupus erythematosus: differential diagnosis of lupus pleuritis BY Choi1, MJ Yoon1, K Shin2, YJ Lee3 and YW Song1,4 1
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; 2Department of Internal Medicine, Seoul National University Borame Medical Center, Seoul, Korea; 3Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea; and 4Department of Molecular Medicine and Biopharmaceutical Sciences, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
We investigated the clinical characteristics of pleural effusion in systemic lupus erythematosus (SLE). A prospective analysis of 17 SLE patients with pleural effusion (seven lupus pleuritis, eight transudative effusions and two parapneumonic effusions) was performed. Thirty non-SLE patients with pleural effusion were recruited as controls. A pleural fluid ANA titer 1:160 was found in 8/17 (47.1%) SLE patients and none of the 30 non-SLE patients (p ¼ 0.0001). Pleural fluid to serum C3 ratios were significantly lower in SLE than in non-SLE (median (minimum– maximum) 0.29 (0.03–0.43) versus 0.52 (0.26–0.73), p ¼ 0.0002). Among SLE patients, pleural fluid ANA titers 1:160 were more frequently found in patients with lupus pleuritis than in those with pleural effusion from causes other than lupus itself (85.7% versus 20.0%, p ¼ 0.0152). Serum CRP levels were significantly increased in patients with lupus pleuritis compared with SLE patients with transudative pleural effusion (2.30 (0.30–5.66) versus 0.7 (0.12–1.47) mg/dl, p ¼ 0.0062). In conclusion, pleural fluid ANA titer and serum CRP levels are significantly increased in lupus pleuritis. Lupus (2015) 24, 321–326. Key words: Systemic lupus erythematosus; pleural effusion; anti-nuclear antibody; lupus pleuritis; C-reactive protein; complement
Introduction Pleuritis is the most common pulmonary manifestation of systemic lupus erythematosus (SLE). Pleuritic chest pain is present in 45–60% of patients with SLE; the pain may or may not be associated with pleural effusion.1 Pleural effusion in SLE tends to be bilateral and small to moderate in size, although large effusions may occur.2 In clinical practice, it is important to rule out other causes than lupus itself, such as parapneumonic effusion, pulmonary embolism, nephrotic syndrome, heart failure and malignancy in the pleural effusions of SLE patients because lupus pleuritis may require glucocorticoid therapy. However, in the clinical setting, it is often difficult
Correspondence to: Yeong Wook Song, Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 110-744, Korea. Email: [email protected] Received 20 December 2013; accepted 18 September 2014
to determine whether pleural effusions in SLE patients represent lupus pleuritis. In the present study, we investigated the clinical characteristics of pleural effusions in SLE and nonSLE patients, and analyzed the differences between lupus pleuritis and pleural effusions from other causes in SLE patients.
Materials and methods Study subjects We prospectively collected data from 17 SLE patients with pleural effusion (mean age standard deviation (SD) 38.4 16.3 years) treated at Seoul National University Hospital from June 1999 to May 2011. The patients fulfilled the American College of Rheumatology 1997 revised classification criteria for SLE.3 A clinical diagnosis of lupus pleuritis was defined when the SLE patient had exudative pleural effusion and no other causes for the pleural effusion could be found. Thirty non-SLE patients
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
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10.1177/0961203314555171
Characteristics of lupus pleuritis BY Choi et al.
322
with pleural effusion (18 female and 12 male; 40.4 11.5 years) were also recruited to determine whether the titer of ANA and complement levels in pleural fluid can distinguish SLE from non-SLE. The study was approved by the hospital’s ethical committee and written informed consent was obtained from all participants. Clinical and laboratory assessment Disease activity in SLE patients was measured using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).4 All patients had laboratory investigations, including a complete blood count, ESR, CRP, serum ANA titer and complement levels (C3 and C4), at the time of thoracentesis. SLE patients were examined for autoantibodies, including anti-dsDNA, antiSmith, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin IgM and IgG, and lupus anticoagulant. Pleural fluid analysis Thoracentesis was performed in all patients. Among those who had multiple thoracenteses, only the first pleural specimen was used for the analysis. Laboratory analyses included biochemical examinations of protein, glucose and lactate dehydrogenase (LDH), pH, cell count and differentiation, bacterial culture, adenosine deaminase (ADA) and cytology. Complement C3 and C4 levels were also measured in pleural fluid samples. The ANA test was performed by an indirect immunofluorescent antibody method with the HEp-2 cell line as a substrate. The test was considered positive at a titer 1:40. An effusion was determined to be an exudate if one of the following criteria was present: 1) the ratio of pleural fluid protein to serum protein exceeded 0.5; 2) the ratio of pleural fluid LDH to serum LDH exceeded 0.6; or 3) pleural fluid LDH was greater than two-thirds of the upper limit of normal. Pleural effusions meeting none of the criteria were considered transudates.5 Statistical analyses Data are presented as the mean SD or median (minimum–maximum), as appropriate. The Mann–Whitney U-test was performed to compare the median values in cases where the data were not normally distributed. Categorical variables were compared using chi-squared or Fisher’s exact test. A p-value 38 C) were reported in 10/17 patients (58.9%) and 12/17 patients (70.6%), respectively. Nine SLE patients had bilateral pleural effusion, while eight patients had unilateral pleural effusion (five right-sided effusions and three left-sided effusions). In all except two patients, pleural effusions were small to moderate in size (25 mm/h) was observed in six of seven patients with lupus pleuritis, there was no statistically significant difference between SLE patients with lupus pleuritis and transudative pleural effusion. In contrast, serum CRP levels were significantly increased in patients with lupus pleuritis compared with those in SLE patients with transudative pleural effusion (2.30 (0.30–5.66) versus 0.71 (0.12–1.47) mg/dl, p ¼ 0.0062). However, serum CRP levels did not differ between SLE patients with lupus pleuritis and parapneumonic effusion. All seven patients with active lupus pleuritis responded to therapy with a moderate dose of glucocorticoids (prednisolone, 22.5 8.75 mg/day) and did not receive any immunosuppressive agents. The median duration of lupus pleuritis was 1.2 months (0.5–4 months). Differential features of pleural effusions between SLE and non-SLE patients Table 3 presents the causes of pleural effusions in SLE and non-SLE patients. In the SLE patients
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Table 1 Clinical and laboratory characteristics of 17 SLE patients with pleural effusion according to its cause
Age (years) Gender (female : male) Duration of the disease (months) Cough Pleuritic chest pain Fever (>38 C) SLEDAI ESR (mm/h) CRP (mg/dl) Anti-dsDNA antibody Anti-Sm antibody Anti-cardiolipin IgM antibody Anti-cardiolipin IgG antibody Lupus anticoagulant Anti-SSA/Ro antibody Anti-SSB/La antibody
Lupus pleuritis (n ¼ 7)
Transudative effusion (n ¼ 8)
Parapneumonic effusion (n ¼ 2)
31.0 (22.0–51.0)a 5:2 23.0 (1.0–120.0) 5 (71.4%) 4 (57.1%) 4 (57.1%) 7.0 (5.0–11.0) 73.0 (49–129) 2.30 (0.30–5.66)b 6 (85.7%) 2 (28.6%) 0 (0%) 3 (42.9%) 1 (14.3%) 4 (57.1%) 3 (42.9%)
32.5 (24.0–54.0) 8:0 43.0 (1.0–140.0) 6 (75.0%) 4 (50.0%) 6 (75.0%) 10.5 (7.0–14.0) 80.5 (9.0–115.0) 0.71 (0.12–1.47) 7 (87.5%) 3 (37.5%) 1 (12.5%) 2 (25.0%) 3 (37.5%) 2 (25.0%) 1 (12.5%)
43.5 (34.0–53.0) 2:0 75.0 (30.0–120.0) 2 (100%) 2 (100%) 2 (100%) 1.5 (1.0–2.0) 119.5 (110–129) 11.41 (4.06–18.76) 2 (100%) 0 (0%) 1 (50.0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Anti-dsDNA: anti-double-stranded DNA; anti-Sm: anti-Smith; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; SLE: systemic lupus erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. a Median (minimum–maximum). b p ¼ 0.0062 (lupus pleuritis versus transudative effusion by Mann–Whitney test).
Table 2 Pleural fluid characteristics in 17 SLE patients with pleural effusion Lupus pleuritis (n ¼ 7) Total white cell counts (/mm3) PMN predominant Lymphocyte predominant Mononuclear predominant pH Protein LDH (IU/l) Glucose (mg/dl) ADA (IU/l) Number of elevated ADA (>45 IU/l) Pleural fluid to serum protein ratio Pleural fluid to serum LDH ratio Pleural fluid to serum glucose ratio High pleural fluid ANA titer (1:160) Pleural fluid to serum ANA ratio 1 Pleural fluid to serum anti-dsDNA ratio Pleural fluid LE cells
700 2 0 5 7.33 3.5 333 114 21 2 0.53 0.87 1.06 6 6 0.26 3
(160–1800)a (28.6%) (0%) (71.4%) (7.27–7.47) (3.1–5.2) (189–526) (87–168) (11–102) (28.6%) (0.44–0.87)b (0.47–1.74)b (0.68–1.61) (85.7%)c (85.7%) (0.03–0.51) (42.9%)
Transudative effusion (n ¼ 8)
Parapneumonic effusion (n ¼ 2)
180 0 1 7 7.46 1.5 82 144 14 1 0.30 0.25 1.08 1 4 0.11 2
13,350 2 0 0 7.18 3.85 3275 61 16 0 0.62 3.45 0.61 1 2 0.22 0
(40–1200) (0%) (12.5%) (87.5%) (7.30–7.88) (0.61–2.32) (33–135) (101–172) (2–58) (12.5%) (0.10–0.41) (0.09–0.46) (0.88–1.49) (12.5%) (50.0%) (0.02–0.48) (25.0%)
(8700–18,000) (100%) (0%) (0%) (7.08–7.28) (3.80–3.95) (423–6126) (49–72) (11–24) (0%) (0.54–0.70) (1.47–5.43) (0.34–0.89) (50.0%) (100%) (0.15–0.29) (0%)
ADA: adenosine deaminase; ANA: anti-nuclear antibody; anti-ds DNA: anti-double-stranded DNA; LE cell: lupus erythematosus cell; LDH: lactate dehydrogenase; PMN: polymorphonuclear; SLE: systemic lupus erythematosus; WBC: white blood cell. a Median (minimum–maximum). b p < 0.0001 (lupus pleuritis versus transudative effusion by Mann–Whitney test). c p ¼ 0.0101 (lupus pleuritis versus transudative effusion by Fisher’s exact test).
with pleural effusion, compared with non-SLE patients, hematologic manifestations such as leukopenia (
CONCISE REPORT
Characteristics of pleural effusions in systemic lupus erythematosus: differential diagnosis of lupus pleuritis BY Choi1, MJ Yoon1, K Shin2, YJ Lee3 and YW Song1,4 1
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; 2Department of Internal Medicine, Seoul National University Borame Medical Center, Seoul, Korea; 3Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea; and 4Department of Molecular Medicine and Biopharmaceutical Sciences, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
We investigated the clinical characteristics of pleural effusion in systemic lupus erythematosus (SLE). A prospective analysis of 17 SLE patients with pleural effusion (seven lupus pleuritis, eight transudative effusions and two parapneumonic effusions) was performed. Thirty non-SLE patients with pleural effusion were recruited as controls. A pleural fluid ANA titer 1:160 was found in 8/17 (47.1%) SLE patients and none of the 30 non-SLE patients (p ¼ 0.0001). Pleural fluid to serum C3 ratios were significantly lower in SLE than in non-SLE (median (minimum– maximum) 0.29 (0.03–0.43) versus 0.52 (0.26–0.73), p ¼ 0.0002). Among SLE patients, pleural fluid ANA titers 1:160 were more frequently found in patients with lupus pleuritis than in those with pleural effusion from causes other than lupus itself (85.7% versus 20.0%, p ¼ 0.0152). Serum CRP levels were significantly increased in patients with lupus pleuritis compared with SLE patients with transudative pleural effusion (2.30 (0.30–5.66) versus 0.7 (0.12–1.47) mg/dl, p ¼ 0.0062). In conclusion, pleural fluid ANA titer and serum CRP levels are significantly increased in lupus pleuritis. Lupus (2015) 24, 321–326. Key words: Systemic lupus erythematosus; pleural effusion; anti-nuclear antibody; lupus pleuritis; C-reactive protein; complement
Introduction Pleuritis is the most common pulmonary manifestation of systemic lupus erythematosus (SLE). Pleuritic chest pain is present in 45–60% of patients with SLE; the pain may or may not be associated with pleural effusion.1 Pleural effusion in SLE tends to be bilateral and small to moderate in size, although large effusions may occur.2 In clinical practice, it is important to rule out other causes than lupus itself, such as parapneumonic effusion, pulmonary embolism, nephrotic syndrome, heart failure and malignancy in the pleural effusions of SLE patients because lupus pleuritis may require glucocorticoid therapy. However, in the clinical setting, it is often difficult
Correspondence to: Yeong Wook Song, Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 110-744, Korea. Email: [email protected] Received 20 December 2013; accepted 18 September 2014
to determine whether pleural effusions in SLE patients represent lupus pleuritis. In the present study, we investigated the clinical characteristics of pleural effusions in SLE and nonSLE patients, and analyzed the differences between lupus pleuritis and pleural effusions from other causes in SLE patients.
Materials and methods Study subjects We prospectively collected data from 17 SLE patients with pleural effusion (mean age standard deviation (SD) 38.4 16.3 years) treated at Seoul National University Hospital from June 1999 to May 2011. The patients fulfilled the American College of Rheumatology 1997 revised classification criteria for SLE.3 A clinical diagnosis of lupus pleuritis was defined when the SLE patient had exudative pleural effusion and no other causes for the pleural effusion could be found. Thirty non-SLE patients
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at GEORGIAN COURT UNIV on March 4, 2015
10.1177/0961203314555171
Characteristics of lupus pleuritis BY Choi et al.
322
with pleural effusion (18 female and 12 male; 40.4 11.5 years) were also recruited to determine whether the titer of ANA and complement levels in pleural fluid can distinguish SLE from non-SLE. The study was approved by the hospital’s ethical committee and written informed consent was obtained from all participants. Clinical and laboratory assessment Disease activity in SLE patients was measured using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).4 All patients had laboratory investigations, including a complete blood count, ESR, CRP, serum ANA titer and complement levels (C3 and C4), at the time of thoracentesis. SLE patients were examined for autoantibodies, including anti-dsDNA, antiSmith, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin IgM and IgG, and lupus anticoagulant. Pleural fluid analysis Thoracentesis was performed in all patients. Among those who had multiple thoracenteses, only the first pleural specimen was used for the analysis. Laboratory analyses included biochemical examinations of protein, glucose and lactate dehydrogenase (LDH), pH, cell count and differentiation, bacterial culture, adenosine deaminase (ADA) and cytology. Complement C3 and C4 levels were also measured in pleural fluid samples. The ANA test was performed by an indirect immunofluorescent antibody method with the HEp-2 cell line as a substrate. The test was considered positive at a titer 1:40. An effusion was determined to be an exudate if one of the following criteria was present: 1) the ratio of pleural fluid protein to serum protein exceeded 0.5; 2) the ratio of pleural fluid LDH to serum LDH exceeded 0.6; or 3) pleural fluid LDH was greater than two-thirds of the upper limit of normal. Pleural effusions meeting none of the criteria were considered transudates.5 Statistical analyses Data are presented as the mean SD or median (minimum–maximum), as appropriate. The Mann–Whitney U-test was performed to compare the median values in cases where the data were not normally distributed. Categorical variables were compared using chi-squared or Fisher’s exact test. A p-value 38 C) were reported in 10/17 patients (58.9%) and 12/17 patients (70.6%), respectively. Nine SLE patients had bilateral pleural effusion, while eight patients had unilateral pleural effusion (five right-sided effusions and three left-sided effusions). In all except two patients, pleural effusions were small to moderate in size (25 mm/h) was observed in six of seven patients with lupus pleuritis, there was no statistically significant difference between SLE patients with lupus pleuritis and transudative pleural effusion. In contrast, serum CRP levels were significantly increased in patients with lupus pleuritis compared with those in SLE patients with transudative pleural effusion (2.30 (0.30–5.66) versus 0.71 (0.12–1.47) mg/dl, p ¼ 0.0062). However, serum CRP levels did not differ between SLE patients with lupus pleuritis and parapneumonic effusion. All seven patients with active lupus pleuritis responded to therapy with a moderate dose of glucocorticoids (prednisolone, 22.5 8.75 mg/day) and did not receive any immunosuppressive agents. The median duration of lupus pleuritis was 1.2 months (0.5–4 months). Differential features of pleural effusions between SLE and non-SLE patients Table 3 presents the causes of pleural effusions in SLE and non-SLE patients. In the SLE patients
Lupus Downloaded from lup.sagepub.com at GEORGIAN COURT UNIV on March 4, 2015
Characteristics of lupus pleuritis BY Choi et al.
323
Table 1 Clinical and laboratory characteristics of 17 SLE patients with pleural effusion according to its cause
Age (years) Gender (female : male) Duration of the disease (months) Cough Pleuritic chest pain Fever (>38 C) SLEDAI ESR (mm/h) CRP (mg/dl) Anti-dsDNA antibody Anti-Sm antibody Anti-cardiolipin IgM antibody Anti-cardiolipin IgG antibody Lupus anticoagulant Anti-SSA/Ro antibody Anti-SSB/La antibody
Lupus pleuritis (n ¼ 7)
Transudative effusion (n ¼ 8)
Parapneumonic effusion (n ¼ 2)
31.0 (22.0–51.0)a 5:2 23.0 (1.0–120.0) 5 (71.4%) 4 (57.1%) 4 (57.1%) 7.0 (5.0–11.0) 73.0 (49–129) 2.30 (0.30–5.66)b 6 (85.7%) 2 (28.6%) 0 (0%) 3 (42.9%) 1 (14.3%) 4 (57.1%) 3 (42.9%)
32.5 (24.0–54.0) 8:0 43.0 (1.0–140.0) 6 (75.0%) 4 (50.0%) 6 (75.0%) 10.5 (7.0–14.0) 80.5 (9.0–115.0) 0.71 (0.12–1.47) 7 (87.5%) 3 (37.5%) 1 (12.5%) 2 (25.0%) 3 (37.5%) 2 (25.0%) 1 (12.5%)
43.5 (34.0–53.0) 2:0 75.0 (30.0–120.0) 2 (100%) 2 (100%) 2 (100%) 1.5 (1.0–2.0) 119.5 (110–129) 11.41 (4.06–18.76) 2 (100%) 0 (0%) 1 (50.0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Anti-dsDNA: anti-double-stranded DNA; anti-Sm: anti-Smith; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; SLE: systemic lupus erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. a Median (minimum–maximum). b p ¼ 0.0062 (lupus pleuritis versus transudative effusion by Mann–Whitney test).
Table 2 Pleural fluid characteristics in 17 SLE patients with pleural effusion Lupus pleuritis (n ¼ 7) Total white cell counts (/mm3) PMN predominant Lymphocyte predominant Mononuclear predominant pH Protein LDH (IU/l) Glucose (mg/dl) ADA (IU/l) Number of elevated ADA (>45 IU/l) Pleural fluid to serum protein ratio Pleural fluid to serum LDH ratio Pleural fluid to serum glucose ratio High pleural fluid ANA titer (1:160) Pleural fluid to serum ANA ratio 1 Pleural fluid to serum anti-dsDNA ratio Pleural fluid LE cells
700 2 0 5 7.33 3.5 333 114 21 2 0.53 0.87 1.06 6 6 0.26 3
(160–1800)a (28.6%) (0%) (71.4%) (7.27–7.47) (3.1–5.2) (189–526) (87–168) (11–102) (28.6%) (0.44–0.87)b (0.47–1.74)b (0.68–1.61) (85.7%)c (85.7%) (0.03–0.51) (42.9%)
Transudative effusion (n ¼ 8)
Parapneumonic effusion (n ¼ 2)
180 0 1 7 7.46 1.5 82 144 14 1 0.30 0.25 1.08 1 4 0.11 2
13,350 2 0 0 7.18 3.85 3275 61 16 0 0.62 3.45 0.61 1 2 0.22 0
(40–1200) (0%) (12.5%) (87.5%) (7.30–7.88) (0.61–2.32) (33–135) (101–172) (2–58) (12.5%) (0.10–0.41) (0.09–0.46) (0.88–1.49) (12.5%) (50.0%) (0.02–0.48) (25.0%)
(8700–18,000) (100%) (0%) (0%) (7.08–7.28) (3.80–3.95) (423–6126) (49–72) (11–24) (0%) (0.54–0.70) (1.47–5.43) (0.34–0.89) (50.0%) (100%) (0.15–0.29) (0%)
ADA: adenosine deaminase; ANA: anti-nuclear antibody; anti-ds DNA: anti-double-stranded DNA; LE cell: lupus erythematosus cell; LDH: lactate dehydrogenase; PMN: polymorphonuclear; SLE: systemic lupus erythematosus; WBC: white blood cell. a Median (minimum–maximum). b p < 0.0001 (lupus pleuritis versus transudative effusion by Mann–Whitney test). c p ¼ 0.0101 (lupus pleuritis versus transudative effusion by Fisher’s exact test).
with pleural effusion, compared with non-SLE patients, hematologic manifestations such as leukopenia (
